The interplay between mitochondria-endoplasmic reticulum contacts and Alzheimer’s disease

Abstract

Even though Alzheimer’s disease (AD) was first described more than 100 years ago, we still have no treatment preventing the ongoing neurodegenerative process. Two major pathological hallmarks have been connected to AD: extracellular amyloid plaques (constituted by amyloid β-peptide – Aβ) and neurofibrillary tangles. Several biological processes have been shown to be altered in AD including mitochondrial functions, autophagosome formation and calcium (Ca2+) homeostasis. Interestingly, all these processes have been shown to be regulated in mitochondria-endoplasmic reticulum contact sites (MERCS). Moreover, both the activity and the number of these contacts are affected in AD, which could explain the alterations of the biological processes mentioned above. However, it is still unknown if the alteration in MERCS causes the pathology or vice-versa. In this thesis, I have contributed to uncovering some of the mechanisms behind the interplay between MERCS and AD.

• In Study I we show that the number of MERCS is increased in brain biopsies of demented patients and that there is a reversed correlation between MERCS and Mini Mental State Examination (MMSE) scores. In the same study, we show that the number of MERCS positively correlate with aging and ventricular Aβ42 levels; • In Study II we show that Aβ increases the number of MERCS in different models, leading to alteration in autophagosome formation and mitochondrial function; • In Study III we show that the increase of MERCS, through acute knock-down of Mitofusin 2, leads to decreased levels of both Aβ40 and Aβ42 due to impaired g-secretase assembly and activity; • In Study IV we show that the translocase of the outer mitochondrial membrane (TOM) receptor protein TOM70 modulates Ca2+ shuttling from ER to mitochondria via IP3R3 at MERCS.

Altogether, these studies contributed to unravel the role of MERCS in AD. We show that MERCS dynamics changes throughout ageing and is accentuated in AD pathology, affecting several biological processes vital for overall cellular function. We believe this increase of MERCS could either trigger the neurodegenerative processes underlying AD or being an attempt to rescue neuronal dysfunctions. Moreover, MERCS modulation affects Aβ levels, which makes us believe that MERCS and Aβ regulate each other in a reciprocal manner.